Anti-Tuberculosis Compounds

pharmaceuticals
Review
Advances in Drug Discovery of New Antitubercular
Multidrug-Resistant Compounds †
Guilherme Felipe dos Santos Fernandes 1,2 , Chung Man Chin 2 and Jean Leandro Dos Santos 1,2, *
1 Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800060, Brazil;
guilhermefelipe@outlook.com
2 School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara 14800903, Brazil;
chungmanchin@gmail.com
* Correspondence: santosjl@fcfar.unesp.br; Tel.: +55-16-3301-6972
† The best presentation at the 2nd International Electronic Conference on Medicinal Chemistry.
Academic Editor: Jean Jacques Vanden Eynde

Received: 4 April 2017; Accepted: 29 May 2017; Published: 1 June 2017
Abstract: Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is
according to the World Health Organization (WHO) the infectious disease responsible for the
highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB)
and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment
against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug
discovery becomes alarming when it is considered that the number of new drugs does not increase
proportionally to the emergence of drug resistance. In this review, we will demonstrate the current
advances in antitubercular drug discovery, focusing on the research of compounds with potent
antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with
minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last
4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.
Keywords: tuberculosis; drug discovery; antitubercular compounds; multidrug-resistant tuberculosis
1. Introduction
According to the World Health Organization (WHO), tuberculosis (TB) is the infectious disease
responsible for the highest number of deaths worldwide, surpassing even the number of deaths
caused by the human immunodeficiency virus (HIV). The last surveys conducted by WHO pointed
out 9.6 million new cases of the disease and 2 million deaths in 2015 [1]. In addition, the emergence
and increase of multidrug-resistant (MDR; defined as resistant as a minimum to rifampicin (RMP) and
isoniazid (INH)) and extensively drug-resistant (XDR; defined as MDR plus additional resistance to at
least one fluoroquinolone and one second-line injectable drug) strains of Mycobacterium tuberculosis
(Mtb) have been alarming authorities around the world. These tuberculosis strains presents low cure
rates and high mortality rates due to difficulties in the treatment [2,3]. Furthermore, cases of totally
drug-resistant tuberculosis (TDR-TB) have been reported in the clinic [4,5].
Over the last few years, progress has been made in the search for new anti-TB compounds [6,7].
The current drug pipeline shows ten drug candidates under preclinical and early phase 1 development
for drug-sensitive and/or drug-resistant tuberculosis. Regarding MDR-TB, the drug pipeline presents
six compounds in phase 2 and 3 trials. Bedaquiline (Sirturo® , Janssen Therapeutics, Titusville, NJ, USA)
and delamanid (Deltyba® , Otsuka Pharmaceutical, Tokyo, Japan) remain in trial phase 3; despite their
approval in several countries justified by the emergency caused by MDR-TB. Sutezolid and pretomanid
are, in phase 2 and 3 trials, respectively. The repurposed drugs clofazimine and levofloxacin are in
phase 3 and 2 trials, respectively [8,9].
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Pharmaceuticals 2017, 10, x 2 of 17
Sutezolid and pretomanid are, in phase 2 and 3 trials, respectively. The repurposed drugs clofazimine
and levofloxacin are in phase 3 and 2 trials, respectively [8,9].
Despite the recent advances, strains resistant to these new molecules have already been2reported
Pharmaceuticals 2017, 10, 51 of 17
[10–12] reinforcing the urgent need to develop novel drugs for tuberculosis treatment. Indeed, the
research of new drugs against TB plays a crucial role in reducing the incidence and mortality
necessaryDespite
to achievethe recent
global advances,
worldwide strains
goals resistant to these
established by thenew
WHO molecules
[1]. have already been
reported [10–12] reinforcing the urgent need to develop novel drugs for tuberculosis treatment. Indeed,
Therefore, this review article aims to create new perspectives to design and develop new anti-
the research of new drugs against TB plays a crucial role in reducing the incidence and mortality
TB drugs against multi-drug resistant strains. We will focus on the challenges and advances in
necessary to achieve global worldwide goals established by the WHO [1].
antitubercular
Therefore, drug thisdiscovery involving
review article aims toMDR-TB.
create new In perspectives
order to describe
to designthose most promising
and develop new
compounds, we included here only active compounds against MDR-TB with minimum
anti-TB drugs against multi-drug resistant strains. We will focus on the challenges and advances inhibitory
concentrations (MICs)
in antitubercular inferior
drug to 11 µM
discovery and low
involving toxicityInpublished
MDR-TB. in the last
order to describe 4 years
those mostinpromising
the following
databases: PubMed, Web of Science and Scopus. All MIC values against
compounds, we included here only active compounds against MDR-TB with minimum inhibitoryMDR-TB strains presented
herein were converted
concentrations (MICs) toinferior
µM in toorder
11 µMto and
establish a comparison
low toxicity publishedamong the4 compounds.
in the last years in the following
databases: PubMed, Web of Science and Scopus. All MIC values against MDR-TB strains presented
herein were converted
2. Antituberculosis to µM in order to establish a comparison among the compounds.
Compounds
Roh
2. and coworkers
Antituberculosis reported a series of 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and
Compounds
thiadiazoles
Roh and coworkers potent
derivatives with reportedactivity against
a series of replicating and nonreplicating Mycobacterium
3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles
tuberculosis. Compounds
and thiadiazoles (1) and (2)
derivatives (Figure
with 1) were
potent the most
activity promising
against in this
replicating andseries and presented
nonreplicating
MICMycobacterium
90 values against several MDR
tuberculosis. strains below
Compounds 0.25
(1) and (2)μM. Moreover,
(Figure 1) werethese
the compounds
most promising haveinbeen
shown to be active against dormant mycobacteria using a luciferase assay. In
this series and presented MIC90 values against several MDR strains below 0.25 µM. Moreover, these vitro cytotoxicity
studies against have
compounds mammalian
been showncell to
lines and isolated
be active human mycobacteria
against dormant hepatocytes usingshowed low toxicity
a luciferase assay.with
In vitro cytotoxicity studies against mammalian cell lines and isolated human
inhibitory concentration (IC50) values above 20 μM. Both compounds also did not exhibit mutagenic hepatocytes showed
low and
activity toxicity withagainst
activity inhibitory concentration
several (IC50fungi.
bacteria and ) values above 20 µM.studies
Furthermore, Both compounds
were performedalso didwhich
not exhibit mutagenic activity and activity against several bacteria and fungi.
attempted to characterize the possible target of the compounds. In vitro studies suggested that Furthermore, studies
were performed which attempted to characterize the possible target of the compounds. In vitro
compounds (1) and (2) could act inhibiting the synthesis of nucleic acids [13]. The same research
studies suggested that compounds (1) and (2) could act inhibiting the synthesis of nucleic acids [13].
group has reported a new series of 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols
The same research group has reported a new series of 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols
as promising antitubercular agents. They have discovered compounds (3) and (4) (Figure 1) as highly
and tetrazole-5-thiols as promising antitubercular agents. They have discovered compounds (3) and
potent
(4) and selective
(Figure derivatives
1) as highly against
potent and seven
selective MDR andagainst
derivatives XDR seven
strainsMDR
withandMIC 90 values below 0.5
XDR strains with
μM. MICIn 90addition, these
values below compounds
0.5 µM. In addition, exhibited low cytotoxicity
these compounds exhibited lowagainst human
cytotoxicity hepatocellular
against human
carcinoma
hepatocellular carcinoma (HuH7), human epidermoid carcinoma (A431), Madin-Darby canine kidney cells
(HuH7), human epidermoid carcinoma (A431), Madin-Darby canine kidney
(MDCK), human hepatocellular
cells (MDCK), carcinoma
human hepatocellular (HepG2)
carcinoma cell cell
(HepG2) lines, with
lines, IC50
with ICabove
50 above3030μMµM[14].
[14].
Figure
Figure1.1.Nitro-containing compounds
Nitro-containing compounds with with antituberculosis
antituberculosis activity.
activity. MIC: MIC:
minimum minimum
inhibitory inhibitory
concentration.
concentration.
Oxazolidinone is an important class of antibiotic used for treatment of infections caused by

Gram-positive pathogens, being the drug linezolid the main representative of this class [15]. This
Pharmaceuticals 2017, 10, 51 3 of 17
Oxazolidinone
Pharmaceuticals 2017, 10, xis an important class of antibiotic used for treatment of infections caused 3 of 17
by Gram-positive pathogens, being the drug linezolid the main representative of this class [15].
This scaffold
scaffold acts through
acts through the inhibition
the inhibition of protein
of protein synthesis
synthesis by binding
by binding to theto50S
the ribosomal
50S ribosomal subunit
subunit and
and blocking the binding of transfer RNA (tRNA) [16]. Researchers from AstraZeneca ® (AstraZeneca
blocking the binding of transfer RNA (tRNA) [16]. Researchers from ®
R&D,
R&D, Bangalore, India) have identified an oxazolidinone derivative, namely AZD5847 (5) (Figure 2),
with
with outstanding
outstandingantitubercular
antitubercular activity against
activity a panel
against of several
a panel clinicalclinical
of several of Mtb with
isolatesisolates of Mtbdifferent
with
resistance profiles, including single drug-resistant strains. AZD5847 showed
different resistance profiles, including single drug-resistant strains. AZD5847 showed improved improved extracellular
and intracellular
extracellular andactivity compared
intracellular to linezolid,
activity comparedexhibiting MICexhibiting
to linezolid, 90 values in a range
MIC of 0.13
90 values in aand 1 µM
range of
in theand
0.13 tested
1 μM strains
in theand a reduction
tested strains and of 1-log-unit
a reductioninofmacrophage
1-log-unit inintracellular
macrophagebacilli. Furthermore,
intracellular bacilli.
the authors also
Furthermore, thedemonstrated that this compound
authors also demonstrated that this(5) also acts (5)
compound through thethrough
also acts inhibition
the of protein
inhibition
synthesis
of protein[17]. AZD5847
synthesis [17]. was
AZD5847clinically
was tested as an
clinically antimycobacterial
tested drug in a drug
as an antimycobacterial phasein2;ahowever,
phase 2;
several adverse effects were observed, including serious hepatic and
however, several adverse effects were observed, including serious hepatic and haematologicalhaematological toxicities [18].
Wei and coworkers also reported a series of bis-oxazolidinone derivatives
toxicities [18]. Wei and coworkers also reported a series of bis-oxazolidinone derivatives with with antitubercular activity.
Compound
antitubercular (6) activity.
(Figure 2) exhibited (6)
Compound MIC 90 values
(Figure at valuesMIC
2) exhibited ranging fromat2values
90 values to 8 µM against
ranging several
from 2 to
clinical MDR and XDR-TB strains. In addition, the authors demonstrated
8 μM against several clinical MDR and XDR-TB strains. In addition, the authors demonstrated the the low cytotoxicity of this
compound against
low cytotoxicity monkey
of this compoundfibroblast-like kidney fibroblast-like
against monkey cell (VERO) with IC50cell
kidney above
(VERO) 5000with
µMIC and high
50 above
selectivity
5000 μM and against
highmycobacteria
selectivity against[19]. mycobacteria [19].
Figure 2.
Figure 2. Oxazolidinone
Oxazolidinone derivatives
derivatives as
as antitubercular
antitubercular agents.
agents.
The antitubercular activities of several nitrogen heterocyclic compounds have been extensively
The antitubercular activities of several nitrogen heterocyclic compounds have been extensively
published in the scientific literature. For instance, a series of 1H-benzo[d]imidazole derivatives have
published in the scientific literature. For instance, a series of 1H-benzo[d]imidazole derivatives
been reported to possess promising activity against a clinically isolated strain resistant to p-
have been reported to possess promising activity against a clinically isolated strain resistant to
aminosalicylic acid (PAS), INH, ethambutol (ETB) and RMP. Compound (7) (Figure 3) showed a
p-aminosalicylic acid (PAS), INH, ethambutol (ETB) and RMP. Compound (7) (Figure 3) showed
MIC90 value of 0.75 μM against this wild strain and low cytotoxicity against human non-small lung
a MIC90 value of 0.75 µM against this wild strain and low cytotoxicity against human non-small lung
cancer (A549) and pig kidney epithelial cell line (LLC-PK1) cell lines, with IC50 values of 11.15 and
cancer (A549) and pig kidney epithelial cell line (LLC-PK1) cell lines, with IC50 values of 11.15 and
43.94 μM, respectively [20]. Later, the same authors published a novel series of 1H-
43.94 µM, respectively [20]. Later, the same authors published a novel series of 1H-benzo[d]imidazoles
benzo[d]imidazoles derivatives. Nevertheless, this new series exhibited worse activity than
derivatives. Nevertheless, this new series exhibited worse activity than compound (7). The best
compound (7). The best compound (8) (Figure 3) showed an MIC90 value of 5 μM in the same MDR
compound (8) (Figure 3) showed an MIC90 value of 5 µM in the same MDR strain and IC50 values of
strain and IC50 values of 58 and 7.8 μM against neonatal human dermal fibroblasts (HDFn) and
58 and 7.8 µM against neonatal human dermal fibroblasts (HDFn) and human epidermal keratinocyte
human epidermal keratinocyte progenitors (HEK) cell lines, respectively [21].
progenitors (HEK) cell lines, respectively [21].
Figure
Figure 3.
3. Nitrogen-containing
Nitrogen-containing heterocycles
heterocycles with
with antituberculosis
activity.
Charushin and coworkers have synthesized synthesized a series of fifteen pyrimidine derivatives and
theirantituberculosis
evaluated their antituberculosisactivity
activityagainst
against a clinical
a clinical isolated
isolated MDR-TB
MDR-TB strain
strain resistant
resistant to RMP
to RMP and
and INH.
INH. Compound
Compound (9) (Figure
(9) (Figure 3) has3)shown
has shown the mostthe most
promisingpromising
activityactivity
with MIC with90MIC 90 of
of 0.7 0.7Mice
µM. μM.
Mice toxicity
acute acute toxicity
revealed revealed
a median a median
lethal dose lethal
(LDdose
50 ) of (LD ) of 315
315 50mg/kg formg/kg for this[22].
this molecule molecule [22].
Additional
Additional
studies studies by
performed performed
this same by this same
research groupresearch group have
have described other described
pyrimidineother pyrimidine
derivatives with
derivatives
similar with similaractivity.
antituberculosis antituberculosis
The mostactivity.
promising The most promising
compound (10) (Figurecompound (10) (Figure
3) exhibited an MIC3) 90
exhibited
value an MIC
of 1.95 µM 90 value aofclinically
against 1.95 μM against
isolatedaMDR-TBclinicallystrain
isolated andMDR-TB
LD50 ofstrain and LD
600 mg/kg of 600toxicity
in50acute mg/kg
in acute
using toxicity
mice [23]. using mice [23]. Quinolizidine-related
Quinolizidine-related compounds havecompounds have alsowith
also been reported been reported with
antituberculosis
antituberculosis
activity in a study activity in a fifteen
involving study involving
derivatives. fifteen derivatives.
The series The series
was evaluated was evaluated
against several MDR-TBagainst
several MDR-TB strains. Compound (11) (Figure 3) was the most active
strains. Compound (11) (Figure 3) was the most active in the series with MIC90 of 0.86 µM. In addition, in the series with MIC 90 of
0.86 compound
this μM. In addition, exhibitedthislow
compound
cytotoxicityexhibited
againstlow VEROcytotoxicity
cells withagainst
IC50 ofVERO 68 µM.cells
[24].with IC 50 of 68
μM. [24].
Several nitrogen-containing fused heterocycles play an important role in the anti-TB Medicinal
Several Shirude
Chemistry. nitrogen-containing
and coworkers fused[25]heterocycles
from AstraZenecaplay an®important
(AstraZeneca role in the anti-TB
R&D, Bangalore, Medicinal
India)
Chemistry.
have reported Shirude and coworkers
a promising [25] from
1,4-azaindole AstraZeneca
derivative ® (AstraZeneca R&D, Bangalore, India)
identified after an optimization process [26].
have reported
Compound (12)a (Figure
promising 1,4-azaindole
4) was characterized derivative identified
as a potent after against
derivative an optimization
MDR-TB,process with MIC [26].
90
Compound
values ranging (12)from
(Figure 4) 1.56
0.78 to wasµM characterized as a potent
with low cytotoxicity derivative
against human against
leukemia MDR-TB,
monocytic with(THP-1)
MIC90
values
cells (ICranging
50 > 100from µM).0.78 to 1.56
In vivo μM with
studies werelow cytotoxicity
performed with against
compoundhuman (12)leukemia
in ordermonocytic
to determine (THP-its
1) cells (IC > 100 μM). In vivo studies were performed with compound (12)
efficacy and pharmacokinetics profile. In rats, this molecule was able to reduce the bacterial burden on
50 in order to determine its
efficacy
a and pharmacokinetics
logarithmic scale of 1 log10 colony profile. In rats,units
forming this molecule
(CFUs)/lung was at
able to reduce
300mg −
kg of 1 thebody
bacterial burden
weight, and
on a logarithmic
statistically scale of 1 log10 was
significant dose-dependentefficacy colonyobserved.formingOn the units (CFUs)/lung
other hand, at 300
pharmacokinetic
mg
analysis kg −1
revealed oflow clearance
body weight,
rates, excellent and bioavailability
statisticallyand no significant
interference dose-dependent
with any of the
efficacy wasP450
cytochrome observed.
(CYP450) On isoenzymes.
the other hand, pharmacokinetic
Nevertheless, analysis presented
this compound revealed low clearance
a rapid rates,
metabolism
excellent bioavailability and no interference with any of the cytochrome
in the presence of mouse liver microsomes [25]. Unsuccessful attempts to optimize this compound P450 (CYP450) isoenzymes.
Nevertheless,
have identifiedthis compound
compound (13) as presented
active againsta rapid metabolism
INH-resistant in the
strains; presence
however, withofMIC mouse liver
90 value of
microsomes
14.3 µM [27].[25]. Danac Unsuccessful
and Mangalagiu attempts haveto optimize
reported the this synthesis
compound have
and identified compound
antituberculosis activity (13)
of a
as active
series against
of fused INH-resistant
bipyridine strains;
heterocycles. however,(14)
Compound with MIC904) value
(Figure presentedof 14.3 μM [27].
promising Danac
activity and
against
Mangalagiu
several singlehave reported
resistant Mtb the synthesis
strains, with MICand 90 antituberculosis
values rangingactivity of a series
from 3.3–9.2 of fused bipyridine
µM [28].
heterocycles. Compound (14) (Figure 4) presented promising activity against several single resistant
Mtb strains, with MIC90 values ranging from 3.3–9.2 μM [28].
Pharmaceuticals
Pharmaceuticals 2017,
2017, 10,
10, xx 55 of
of 17
17
Figure
4.4.
Figure
Figure Nitrogen-containing
4.Nitrogen-containing fused
Nitrogen-containingfused heterocycles
heterocycles with
fused heterocycles with potent
potentactivity
potent activityagainst
activity againstmultidrug-resistant
against multidrug-resistant
multidrug-resistant
tuberculosis (MDR-TB). tuberculosis (MDR-TB).
tuberculosis (MDR-TB).
from AstraZeneca ®
Raichurkar
Raichurkar and and coworkers
coworkers also also from AstraZeneca®® (AstraZeneca
from AstraZeneca (AstraZeneca R&D, R&D, Bangalore,
Bangalore, India)India) have have
reported
reported the
the discovery
discovery of of pyrazolopyridones
pyrazolopyridones derivatives
derivatives as as promising
promising
reported the discovery of pyrazolopyridones derivatives as promising antitubercular compounds antitubercular
antitubercular compounds
compounds [29].
[29].
[29]. Initially, they investigated the antituberculosis activity of these compounds against a panel of
Initially,
Initially, they they investigated
investigated the the antituberculosis
antituberculosis activity activity
of these of these
compounds compounds
against aagainst
panel of a panel
sensitiveof
sensitive
and clinical
sensitive and
and clinical
isolated
clinical isolated
single
isolated single
single drug-resistant
drug-resistant strains. Compound
drug-resistant strains.
strains. (15)Compound
(Figure 5)
Compound (15) (Figure
presented
(15) (Figure MIC 5)
5) presented
90 values
presented
MIC
MIC90 90 values
ranging fromranging
values 1.6–3.1from
ranging µM and
from 1.6–3.1
1.6–3.1lowμM
μM and
and low
low cytotoxicity
cytotoxicity against the
cytotoxicity against
human
against the human
theA549
human A549
cell linecell
A549 (ICline
cell 50 160
line (IC
(IC50 160
µM).
50 160
μM).
μM). The authors also demonstrated through biochemical screening and genetic mapping that the
The The
authors authors
also also demonstrated
demonstrated through through biochemical
biochemical screening screening
and and
genetic genetic
mapping mapping
that the that
target
the
target of 0 -epimerase (DprE1),
of
target of compound
compound (15)
(15) is is decaprenylphosphoryl-β-
(15) is decaprenylphosphoryl-β-
compound decaprenylphosphoryl-β- D -ribose-2
DD-ribose-2′-epimerase
-ribose-2′-epimerase (DprE1),
an enzyme
(DprE1), an
an enzyme that
that plays
enzyme that
plays
an an
an important
important
plays role inrole
important the in
role the
the biosynthesis
biosynthesis
in of
of components
of components
biosynthesis components of theof the
the mycobacterial
mycobacterial
of mycobacterialcell wallcell wall
wall [30,31].
cell[30,31]. In
In vitro
[30,31]. In
vitro
drug drug
drug metabolism
vitro metabolism and
and pharmacokinetics
and pharmacokinetics
metabolism properties
pharmacokinetics properties were
were performed
were performed
properties for this for
performed for this
this compound,
compound, that exhibits
compound, that
that
exhibits
exhibits distribution
distribution coefficient
distribution coefficient
(logD) of(logD)
coefficient 3.9 and
(logD) of 3.9
3.9 and
and suboptimal
ofsuboptimal aqueousaqueous
suboptimal solubility
aqueous solubility (1
(1 µM), free
solubility (1 μM), free
plasma
μM), plasma
free protein
plasma
protein
protein binding (1%), and clearance (27 μL/min/kg) [29]. In another work, the synthesis and
binding binding
(1%), and (1%),
clearanceand clearance
(27 µL/min/kg) (27 μL/min/kg)
[29]. In [29].
another In
work, another
the work,
synthesis the
and synthesis
antituberculosis and
antituberculosis
activity activity
activity of of pyrazolo[1,5-a]pyridine-3-carboxamide
of pyrazolo[1,5-a]pyridine-3-carboxamide
antituberculosis derivatives were reported.
pyrazolo[1,5-a]pyridine-3-carboxamide derivatives were
Specifically,
derivatives reported.
werecompound
reported.
Specifically,
(16) (Figure compound
Specifically, 5) has shown
compound (16) (Figure
(16)potent
(Figurein 5) has
has shown
5)vitro potency
shown potent in
in vitro
vitro potency
at nanomolar
potent at
at nanomolar
concentration,
potency nanomolar for concentration,
which MIC90
concentration,
for which
values MIC
ranged values
from 11.1ranged
to 223 from
nM 11.1 to
against 223 nM
several against
clinically several clinically
isolated
for which MIC90 values ranged from 11.1 to 223 nM against several clinically isolated MDR-TB
90 MDR-TB isolated MDR-TB
strains. strains.
In addition,
strains.
In
In addition,
they evaluated
addition, they
they evaluated
the the
the in
in vivo efficacy
evaluated in vivo efficacy
efficacy of
of compound
vivo of compound
(16) in a mouse
compound (16)
(16) in aa mouse
model
in model
infected
mouse model infected
with with
with the
the selectable
infected the
selectable
selectable marker-free autoluminescent Mtb H37Ra, a non-virulent strain. They observed aa
marker-free marker-free
autoluminescent autoluminescent
Mtb H37Ra, a Mtb H37Ra,
non-virulent a non-virulent
strain. They strain.
observed a They observed
bactericidal activity
bactericidal
of
bactericidal activity
this compound,activity of
of this
this compound,
resulting in a reduction
compound, resulting in
in aa reduction
of bacterial
resulting burden using
reduction of
of bacterial
a modified
bacterial burden using
real-time
burden aa modified
usingmonitoring
modified
real-time
real-time monitoring
noninvasive noninvasive
bioluminescence
monitoring noninvasive assaybioluminescence
[32].
bioluminescence assay
assay [32].
[32].
Figure
Figure 5. 5.
Figure Compounds
5.Compounds with
Compoundswith antitubercular
antitubercular activity
withantitubercular activity against
activity againstMDR
against MDRand
MDR andextensively-drug
and extensively-drug resistant
resistant
extensively-drug resistant
tuberculosis (XDR-TB). tuberculosis (XDR-TB).
tuberculosis (XDR-TB).
Xuefu
Xuefu
Xuefu YouYou
Youand and coworkers
andcoworkers
coworkershave have
have identified
identified
identified aa potent
a potent imidazo[1,2-a]pyridine
imidazo[1,2-a]pyridine
potent imidazo[1,2-a]pyridine derivative
derivative against
against
derivative two
against
two
two clinically
clinically isolated
isolated
clinically MDR MDR
isolated strainsstrains
MDR resistant
strains resistant
to INHto
resistant toandINH
INH and
RMP. RMP.
RMP. Compound
andCompound (17) (Figure
Compound (17)
(17)6)(Figure 6)
6) has
has exhibited
(Figure has
exhibited
MIC
exhibited MIC
90 values
MIC values
ranging
90 values
90 ranging
from from
0.09 tofrom
ranging 0.09
0.13 0.09 to
µM and 0.13
lowμM
to 0.13 μM and
in vivo low
and acute in vivo
low intoxicity acute
vivo acute toxicity
in mice in
and rats.
toxicity mice and rats.
Furthermore,
in mice and rats.
Furthermore,
this compoundthis
Furthermore, this compound
exhibited acceptable
compound exhibited acceptable
pharmacokinetic
exhibited pharmacokinetic
acceptable properties, with maximum
pharmacokinetic properties,
serum
properties, with maximum
concentration
with maximum
serum
(C max ) concentration
serum of 225 ng/mL,(C
concentration max)) of
of 225
225 ng/mL,
(Celimination
max elimination
half-life
ng/mL, (T1/2 ) of 1.5
elimination half-life
h and(T
half-life 1/2)) of
of 1.5
(Tclearance
1/2 1.5 hh
ofand clearance
86,284
and mL/h/kg
clearance of
of 86,284
[33].
86,284
mL/h/kg
Castagnolo [33].
mL/h/kg [33]. Castagnolo
and coworkersand
Castagnolo and coworkers
have have
reportedhave
coworkers reported
a series a series
of pyrrole
reported of pyrrole
a seriesderivatives derivatives
of pyrrole designed
derivatives designed
hybrids as
asdesigned of
as
hybrids
hybrids of
of the
the antitubercular
antitubercular drugdrug candidates
candidates BM212
BM212 and and SQ109.
SQ109. They
They obtained
obtained in in the
the first
first generation
generation
aa hybrid
hybrid compound
compound with with MICMIC90 90 value
value ofof 17.8
17.8 μM
μM against
against two
two MDR
MDR clinical
clinical isolates.
isolates. After,
After, using
using

the antitubercular drug candidates BM212 and SQ109. They obtained in the first generation a
molecular
hybrid simplification,
compound
Pharmaceuticals 2017,with the authors
10, x MIC have discovered the second-generation of this hybrid derivative
90 value of 17.8 µM against two MDR clinical isolates. After, using
6 of 17
(compound 18) (Figure 6) as a potent antitubercular agent with MIC 90 value of 1.58 μM. Furthermore,
molecular simplification, the authors have discovered the second-generation of this hybrid derivative
molecular simplification,
this compound was able the authors have discovereddrug
the second-generation of this hybrid derivative
(compound 18) (Figure 6)toasinhibit theantitubercular
a potent mycobacteria effluxMIC
agent with pumpvalue
at potency
of 1.58comparable to that
µM. Furthermore,
(compound 18) (Figure 6) as a potent antitubercular agent with MIC90 90 value of 1.58 μM. Furthermore,
of verapamil
this compound [34].
was able to inhibit the mycobacteria drug efflux pump at potency comparable to that
this compound was able to inhibit the mycobacteria drug efflux pump at potency comparable to that
of verapamil [34].[34].
of verapamil
Figure
Figure 6. Compoundswith
6. Compounds withantitubercular
antitubercular activity
activityagainst
againstMDR-TB.
MDR-TB.
MDR-TB.
Quinoline derivatives
Quinoline and derivatives represent an important class class of heterocyclicin theinmedicinal
the medicinal
Quinoline and and derivatives represent
represent an important
an important of heterocyclic
class of heterocyclic chemistry
in the medicinal
chemistry field because its wide range of biological activities, including antituberculosis [35].
field because its wide range of biological activities, including antituberculosis
chemistry field because its wide range of biological activities, including antituberculosis [35]. [35]. Machado and
Machado and coworkers have reported a series of quinoline derivatives with inhibitory activity
coworkers
Machado havecoworkers
and reported ahave series of quinoline
reported derivatives
a series with derivatives
of quinoline inhibitory activity against a activity
clinical
against a clinical isolate of an MDR-TB strain. Compound (19) (Figure 7) showedwith inhibitory
a potent MIC90 value
isolate
against of
a an MDR-TB
clinical isolate strain.
of an Compound
MDR-TB (19)
strain. (Figure
Compound 7) showed
(19) (Figure
of 0.05 μM and activity against macrophage intracellular mycobacteria. Moreover, 90 a potent
7) showed MIC a value
potent of
MIC
the authors also 0.05 µM
90 value
and activity
of 0.05 μM and
performed against macrophage
activity
metabolic against intracellular
macrophage
stability and drug–drug mycobacteria.
intracellular Moreover,
mycobacteria.
interaction the authors
Moreover,
studies. Compound also
the
(19) performed
authors
exhibited also
metabolic
performed stability
moderate metabolicand drug–drug
metabolic stability interaction
stability inand
the drug–drug
human S9studies.
fraction, Compound
interaction (19) exhibited
with an studies.
in vitro Compound
intrinsic moderate
clearance (Clmetabolic
(19) exhibited
int ) of
stability
14.3in
moderate the human
mL/min/kg
metabolic and S9T1/2
fraction,
stabilityof 21.8 with
min.
in the Inan
human inS9
vitro
addition, intrinsic
this
fraction, clearance
derivative
with andidinnot (Cl
alter
vitro )the
of enzymatic
intrinsic
int 14.3clearance
mL/min/kg
levels(Cl inintand
) of
T14.3 the
1/2 of liver,
mL/min/kg suggesting
21.8 min. and a
In addition,minimal risk
thismin.
T1/2 of 21.8 of
derivativemetabolic
did not
In addition, drug−drug
thisalter interactions
the enzymatic
derivative did not [36].
levels Later,
alterinthe the same
theenzymatic group
liver, suggesting
levels in a
minimalhas risk
the liver, reported
suggesting a novel
of metabolic series−
drug
a minimal of quinoline
drug
risk derivatives
interactions
of metabolic withinteractions
[36]. Later,
drug−drug improved
the same antituberculosis
group the activity.
has reported
[36]. Later, samea group
novel
series Compound
of quinoline (20) derivatives
(Figure 7) exhibited
with a potent MIC
improved 90 value of 1 nM against a clinical isolate of an MDR-
antituberculosis activity. Compound (20) (Figure 7)
has reported a novel series of quinoline derivatives with improved antituberculosis activity.
TB strain with a Clint of 14.8 mL/min/kg and T1/2 of 19.4 min [37].
exhibited
Compound a potent MIC907)value
(20) (Figure of 1 nM
exhibited against
a potent MIC a90clinical
value ofisolate
1 nMof an MDR-TB
against a clinicalstrain
isolatewith a Cl
of an int of
MDR-
14.8 mL/min/kg
TB strain with a Cl and T1/2
int of 14.8ofmL/min/kg
19.4 min [37]. and T1/2 of 19.4 min [37].
Figure 7. Quinoline derivatives with antituberculosis activity.
Ghorpade and coworkers from AstraZeneca® (AstraZeneca R&D, Bangalore, India) have
discovered a quinolone derivative as a promising antituberculosis agent. The authors have assessed
Figure 7. Quinoline derivatives with antituberculosis activity.
activity.
Ghorpade and coworkers from AstraZeneca® (AstraZeneca R&D, Bangalore, India) have
Ghorpade
Pharmaceuticals 2017,and
10, x coworkers from AstraZeneca® (AstraZeneca R&D, Bangalore, India) 7have of 17
several properties
properties ofof the
the lead
leadcompound
compound(21) (21)(Figure
(Figure8),8),including
including mechanism
mechanism of of action
action studies,
studies, in
in vitro/in
vitro/in vivo
vivo pharmacokinetics
pharmacokinetics anddrug
and drugmetabolism.
metabolism.This Thisquinoline
quinoline derivative
derivative presented MIC MIC9090
values ranging
rangingfrom
from0.2 0.2to to 3.12
3.12 μMµM against
against several
several single single drug-resistant
drug-resistant strains.
strains. The showed
The authors authors
showed
that the that the of
target target of compound
compound (21)the
(21) is is the mycobacterial
mycobacterial DprE1
DprE1 enzyme.InInaddition,
enzyme. addition,in in vivo
pharmacokinetics studies
studies pointed
pointedoutoutcompound
compound(21) (21)with
with Cmax
Cmax of 4.9
of 4.9 μM,µM, plasma
plasma clearance
clearance of
of 34.4
34.4 mL/min/kg
mL/min/kg and
and T1/2 of T 1/2h of
0.5 0.5Ah series
[38]. [38]. Aofseries of quinazolinone
quinazolinone derivatives
derivatives have been have been reported,
reported, showing
showing potent antitubercular
potent antitubercular activity
activity [39]. [39]. Compound
Compound (22) (Figure (22) 8)
(Figure 8) exhibited
exhibited MIC90 ofMIC of 6.6
6.6 90μM µM
against
against several MDR and XDR-TB clinical isolates. In addition, the
several MDR and XDR-TB clinical isolates. In addition, the authors suggested that the authors suggested that the Mtb
acetohydroxy-acid
acetohydroxy-acid synthase
synthase(AHAS)
(AHAS)isisthe thetarget
targetofofthese
thesequinazolinone
quinazolinone derivatives
derivatives[39]. AHAS
[39]. AHAS is anis
enzyme
an enzyme thatthat
playsplays
an important
an importantrole inrole
the branched-chain
in the branched-chainamino acids
amino(BCAAs) biosynthetic
acids (BCAAs) pathway
biosynthetic
and its inhibition
pathway seems to be
and its inhibition a potential
seems to be a target for target
potential anti-TBfor drugs [40].drugs [40].
anti-TB
Figure 8. Compounds
Figure 8. Compounds with
with antituberculosis activity.
Compounds that acts through the release of reactive oxygen and nitrogen species, such as
Compounds that acts through the release of reactive oxygen and nitrogen species, such as
furoxan and nitro compounds, have been extensively explored as antituberculosis agents [41–43].
furoxan and nitro compounds, have been extensively explored as antituberculosis agents [41–43].
Brönstrup and coworkers have reported a series of nitrofuran derivatives with selective activity
Brönstrup and coworkers have reported a series of nitrofuran derivatives with selective activity against
against Mtb. Specifically, compound (23) (Figure 9) exhibited MIC90 of 11 μM against two MDR-TB
Mtb. Specifically, compound (23) (Figure 9) exhibited MIC90 of 11 µM against two MDR-TB clinical
clinical isolates. The authors also evaluated the spectrum of activity for compound (23) and they did
isolates. The authors also evaluated the spectrum of activity for compound (23) and they did not
not find activity against a panel of Gram-positive and Gram-negative bacteria [44]. The
find activity against a panel of Gram-positive and Gram-negative bacteria [44]. The nitroimidazole
nitroimidazole class is another important scaffold in the medical chemistry of antituberculosis agents,
class is another important scaffold in the medical chemistry of® antituberculosis agents, especially
especially its main representative, the drug delamanid (Deltyba , Otsuka Pharmaceutical) [45,46]. A
its main representative, the drug delamanid (Deltyba® , Otsuka Pharmaceutical) [45,46]. A series of
series of nitroimidazole derivatives have been reported as presenting an outstanding antituberculosis
nitroimidazole derivatives have been reported as presenting an outstanding antituberculosis activity
activity against an MDR-TB clinical isolate. For instance, the most promising compound (24) (Figure
against an MDR-TB clinical isolate. For instance, the most promising compound (24) (Figure 9)
9) presented a MIC90 of 0.11 μM. The in vivo pharmacokinetics showed a good profile, with Cmax of
presented a MIC90 of 0.11 µM. The in vivo pharmacokinetics showed a good profile, with Cmax of
0.54 μg/mL, T1/2 of 2 h and no CYP inhibition at three different concentrations tested (10, 30 and 100
0.54 µg/mL, T1/2 of 2 h and no CYP inhibition at three different concentrations tested (10, 30 and
μM). In vivo efficacy of compound (24) was assessed using a mice model for acute infection. Using
100 µM). In vivo efficacy of compound (24) was assessed using a mice model for acute infection. Using
an infected mice model, this compound was able to reduce the bacterial burden on a logarithmic scale
an infected mice model, this compound was able to reduce the bacterial burden on a logarithmic scale
of 1.8 log10 CFU at 100 mg kg−1 once daily for 28 days. [47]. Furoxan derivatives also have been
of 1.8 log10 CFU at 100 mg kg−1 once daily for 28 days. [47]. Furoxan derivatives also have been
reported showing its promising application as antitubercular compounds. Specifically, compound
reported showing its promising application as antitubercular compounds. Specifically, compound
(25) (Figure 9) exhibited MIC90 of 7 μM against MDR-TB clinical isolates. Furthermore, the authors
(25) (Figure 9) exhibited MIC90 of 7 µM against MDR-TB clinical isolates. Furthermore, the authors
have demonstrated that this compound may act through the release of nitric oxide [48]. Smith and
have demonstrated that this compound may act through the release of nitric oxide [48]. Smith and
coworkers have discovered a nitrotriazole derivative as a promising antitubercular agent. Compound
coworkers have discovered a nitrotriazole derivative as a promising antitubercular agent. Compound
(26) (Figure 9) showed MIC90 values below 3.9 μM against several single drug-resistant strains. In
(26) (Figure 9) showed MIC90 values below 3.9 µM against several single drug-resistant strains.
addition, compound (26) exhibited intracellular activity against infected J774 macrophages, resulting
In addition, compound (26) exhibited intracellular activity against infected J774 macrophages, resulting
in a reduction of 1.18 log of intracellular bacilli burden [49].
in a reduction of 1.18 log of intracellular bacilli burden [49].
Figure
Figure
Figure 9. Compounds
9. Compounds
9. Compounds with
with antituberculosisactivity
antituberculosis activity that
thatacts
actsthrough
throughthethe
release of reactive
release oxygen
reactive
of reactive oxygen
and nitrogen species.
nitrogen species.
and nitrogen species.
Chibale and coworkers have identified the compound pyrrolo[3,4-c]pyridine-1,3(2H)-dione (27)
Chibale and coworkers have identified the compound pyrrolo[3,4-c]pyridine-1,3(2H)-dione (27)
(Figure 10) through a phenotypic screening with potent antituberculosis activity; however, this
(Figure
(Figure 10)
10) through
through aa phenotypic
phenotypic screening
screening with potent antituberculosis activity; however, this
compound presented drawbacks regarding its with
metabolicpotent antituberculosis
stability. activity;
The optimization of thishowever,
molecule this
compound presented drawbacks regarding its metabolic stability.
stability. The
The optimization
optimization
leads to compound (28) (Figure 10), which demonstrated MIC90 values below 0.6 μM against several of this molecule
leadsclinical
to compound (28) (Figure
(28) good
isolates and (Figure 10), which
10), which
metabolic demonstrated
demonstrated
stability MIC
MIC90
in liver microsomes. 90 values below 0.6
The mycobacterialµM against
μM respiratory several
clinical isolates and
cytochrome bc1 good
good metabolic
andcomplex metabolic stability
was identifiedstability in
as the liver
liver microsomes.
intarget microsomes.
for The mycobacterial
these compounds. Nevertheless, respiratory
mycobacterial respiratory
mouse
cytochrome bc1 complex
pharmacokinetics complex was
studieswas identified
showed as
as the
the target
high clearance
identified and low
target for these
thesecompounds.
forplasma exposure
compounds. Nevertheless,
for compound mouse
(28) [50].
Nevertheless, mouse
In another
pharmacokinetics
pharmacokinetics study, a
studiesseries of
showed twenty-seven
high benzo[d]oxazol-2(3H)-one
clearance
clearance and low plasma derivatives
exposure
plasma exposure for were synthesized.
compound (28) [50].
compound (28)
Specifically,
In another study, compound (29) (Figure 10) exhibited a promising antituberculosis activity against an
study, aa series
series ofof twenty-seven
twenty-seven benzo[d]oxazol-2(3H)-one
benzo[d]oxazol-2(3H)-one derivatives were synthesized.
synthesized.
XDR-TB
Specifically, clinical isolate, with MIC 90 of 11.47 μM. The authors also demonstrated that compound (29)
Specifically, compound
compound (29) (29) (Figure
(Figure 10) 10) exhibited
exhibited aa promising
promising antituberculosis
antituberculosis activity against an
acts through the inhibition of the mycobacterial 2-trans-enoyl-acyl carrier protein reductase (InhA),
XDR-TB clinical isolate, with
XDR-TB clinical isolate, with MIC90 MIC 90 of 11.47 µM.
μM. The authors also demonstrated that compound (29)
a key enzyme involved in the mycolic acid biosynthesis in Mtb [51]. Shuyi Si and coworkers have
acts through the inhibition
inhibition of the
the mycobacterial
mycobacterial 2-trans-enoyl-acyl carrier protein reductase (InhA),
discovered several disubstituted oxazole analogues as potent antituberculosis agents. Among the
a key enzyme
keytwenty-five involved
enzyme involved in the mycolic
the mycolic
compounds evaluated, acid biosynthesis
(30) (Figure in
acid biosynthesis
compound in Mtb
10) Mtb
showed[51].
[51]. Shuyi Siactivity
promising and
and coworkers
with MIC90have
coworkers have
discovered
values several
of 2.2 and disubstituted
disubstituted
4.3 μM against oxazole
XDR-TB analogues
analogues
and MDR-TB, as
as potent
potent antituberculosis
Moreover,agents.
antituberculosis
respectively. agents.
compound Among
(30) the
the
twenty-five
proved compounds
twenty-five to be selectiveevaluated,
compounds evaluated, compound
for Mtb becausecompound (30) (Figure
(30)against
no activity (Figure 10)
10)showed
other showed promising
promising
bacteria was observed activity
[52]. with
activity withMIC
MIC9090
values
values ofof2.2
2.2and
and 4.34.3
µMμM against XDR-TB
against XDR-TB and MDR-TB,
and MDR-TB, respectively. Moreover,
respectively. compound
Moreover, (30) proved
compound (30)
to be selective
proved for Mtb because
to be selective no activity
for Mtb because no against
activity other
against bacteria was observed
other bacteria [52].
was observed [52].
Figure 10. Heterocyclic compounds as promising agents for the treatment of MDR-TB.
Figure 10. Heterocyclic compounds as promising agents for the treatment

treatment of
of MDR-TB.
MDR-TB.
Sulfur-containing heterocycles have been widely exploited as antituberculosis agents [53].

Researches from AstraZeneca® (AstraZeneca R&D, Bangalore, India) have discovered a diarylthiazole
derivative after molecular optimizations in a previously identified hit. Compound (31) (Figure 11)
showed potent antituberculosis activity with MIC90 values below 1.68 µM against several MDR-TB
clinical isolates. In vitro drug metabolism and pharmacokinetics parameters were assessed for
compound (31), which exhibited solubility of 31 µM, mouse plasma protein binding of 17% and
mouse clearance of 170.4 µL/min/mg. Moreover, the authors have characterized the PrrBA as the
molecular target of this derivative [54]. PrrBA is a two-component system composed of the PrrB
histidine kinase and PrrA response regulator and it plays an important role in mycobacterial virulence
and metabolic adaptation to stress [55,56]. In another work, Luoting Yu and coworkers reported a
benzothiazinethione derivative as a potent antitubercular agent [57]. Compound (32) (Figure 11), an
analog of the drug candidate BTZ043 [58], presented MIC90 values below 0.03 µM against several
MDR and XDR-TB clinical isolates. The pharmacokinetics in rats of this compound showed Cmax of
193 ng/mL, T1/2 of 1.45 h and 44.4% of absolute oral bioavailability. Furthermore, compound (32)
demonstrated in vivo efficacy in a mice model, which was able to reduce the Mtb burden in lungs by
3.4 logs CFU [57]. Thiazole and its analogue benzothiazole are also important sulfur-containing
heterocycles with antituberculosis activity. For instance, the synthesis of a series of thirty-four
thiazole derivatives have been reported and their antitubercular activity was assessed against several
single drug-resistant strains. Compound (33) (Figure 11) showed MIC90 values ranging from 7.1 and
12.0 µM [59]. Ramachandran and coworkers at AstraZeneca® (AstraZeneca R&D, Bangalore, India) also
reported benzothiazoles derivatives as antitubercular. They discovered compound (34) (Figure 11) as a
promising antituberculosis agent with MIC90 values below 4.62 µM against several single drug-resistant
isolates. DprE1 was characterized as the target of compound (34). In addition, this compound
demonstrated safety profile with low cytotoxicity against human A549 cell line (IC50 > 100 µM),
negative Ames assay and moderate CYP isoform inhibition [60].
Mahajan and Dhawale reported the synthesis of a series of thiadiazoles derivatives as promising
candidates for resistant tuberculosis treatment. Among the thirty-three compounds synthesized,
compound (35) (Figure 12) showed the best antimycobacterial activity with MIC90 values ranging from
0.08 to 0.66 µM against several MDR and XDR-TB clinical isolates [61]. Thienyl-substituted pyrimidines
derivatives also have been reported with potent activity against an MDR-TB strain. Specifically,
compound (36) (Figure 12) demonstrated MIC90 of 0.4 µM and mouse LD50 of 45 mg/kg [62].
In another study, Kozikowski and coworkers synthesized a series of triclosan derivatives with the
mycobacterial InhA enzyme characterized as the molecular target. Compound (37) (Figure 12)
exhibited MIC90 of 0.7 µM against two MDR-TB strains [63]. Later, the same research group
identified an indole-2-carboxamide derivative designed from a structure-activity relationship analysis
of previously obtained compounds. Compound (38) (Figure 12) showed outstanding antituberculosis
activity against MDR and XDR-TB strains. The MIC90 values for these strains ranged from 0.006 to
0.047 µM. Pharmacokinetics results showed a Cmax of 1.71 µg/mL, Tmax of 4 h, low inhibition in the
tested CYP isoforms (<40%) and negative results in the bacterial reverse mutation assay in Salmonella
typhimurium tester strains. Moreover, the in vivo efficacy of this compound was assessed in a mouse
infection model and it was able to reduce the bacterial burden on a logarithmic scale of 2.12 log10 CFU
at 100 mg kg−1 dosage level in the lungs after 4 weeks of treatment protecting the mice from death.
Altogether, these results pointed out compound (38) as a promising drug candidate for human clinical
trials [64].
Figure
Figure 11.
11. Sulfur-containing
Sulfur-containing heterocycles
heterocycles with
with potent antitubercular activity.
Figure 11. Sulfur-containing heterocycles with potent
potent antitubercular
antitubercular activity.
activity.
Figure 12. Sulfur-containing compounds, triazole and indole as potent anti-TB agents.
Figure 12.
Figure 12. Sulfur-containing compounds, triazole and indole as potent anti-TB
anti-TB agents.
agents.
Indeed, the scientific literature presents several works involving only the synthesis and
Indeed,
Indeed, the
thescientific literature
scientific presents
literature several
presents works works
several involving only the synthesis
involving only the and phenotypic
synthesis and
phenotypic screening of compounds against MDR strains accompanied by in silico studies. Among
screening
phenotypicofscreening
compounds against MDR
of compounds strains
against MDRaccompanied by in silico
strains accompanied by instudies. AmongAmong
silico studies. these
these compounds, several heterocycles and scaffolds are contemplated, including benzo[d]isoxazole
compounds, severalseveral
these compounds, heterocycles and scaffolds
heterocycles are contemplated,
and scaffolds including
are contemplated, benzo[d]isoxazole
including (39) [65],
benzo[d]isoxazole
(39) [65], benzo[b]thiophenes (40) [66], disubstituted piperazine (41) [67], and benzoxazole (42) [68]
(39) [65], benzo[b]thiophenes
benzo[b]thiophenes (40) [66], disubstituted
(40) [66], disubstituted piperazinepiperazine (41)benzoxazole
(41) [67], and [67], and benzoxazole (42) [68]
(42) [68] (Figure 13).
(Figure 13).
(Figure 13).
Figure 13.
Figure 13. Miscellaneous of compounds
Miscellaneous of compounds with
with activity
activity against
against MDR-TB.
MDR-TB.
For instance, compound (39) exhibited MIC90 90 of

of 6.16
6.16 μMµM against an MDR-TB isolate and low
cytotoxicity against
against mouse
mousemacrophage
macrophage(RAW264.7)(RAW264.7)cell celllines
lines with
withICIC
50 of
50 222.92
of 222.92 μM.µM.In addition,
In addition,the
authors
the performed
authors performed dockingdockingstudies on the
studies on mycobacterial
the mycobacterial pantothenate
pantothenate synthetase enzyme
synthetase and
enzyme
compound
and compound(39) showed
(39) showed a good interaction
a good in the
interaction in enzyme
the enzyme activeactive
site with
site withdocking scorescore
docking of −9.2of
kcal/mol
− [65]. This
9.2 kcal/mol [65].enzyme is involved
This enzyme in the biosynthesis
is involved in the biosynthesisof coenzyme A and acyl
of coenzyme A and carrier
acyl protein
carrier
[69]. The[69].
protein benzo[b]thiophene
The benzo[b]thiophene(40) also exhibited potent antituberculosis
(40) also exhibited activity against
potent antituberculosis a multidrug-
activity against a
resistant strain with strain
multidrug-resistant MIC90 withof 8.3MICμM.90Docking studies
of 8.3 µM. on thestudies
Docking DprE1 enzyme
on the DprE1 were performed
enzyme were and
compound (40)
performed and showed
compound a docking score ofa −8.7
(40) showed kcal/mol,
docking scoresuggesting that this enzyme
of −8.7 kcal/mol, suggesting couldthatbethis
the
potentialcould
enzyme molecular
be thetarget [66]. molecular
potential Likewise, compound
target [66]. (41) showed
Likewise, a promising
compound (41)antitubercular
showed a promisingactivity
against an MDR-TB
antitubercular strain
activity withan
against MIC 90 of 2.4strain
MDR-TB μM. InwithvitroMICmicrosome
90 of 2.4 µM.stability
In vitrostudy exhibitedstability
microsome a T1/2 of
14.4 h exhibited
study and low ainhibition
T1/2 of 14.4 of two
h and isoforms of cytochrome
low inhibition P450, namely
of two isoforms CYP3A4 and
of cytochrome P450,CYP2D6.
namely
Moreover,and
CYP3A4 theCYP2D6.
authors suggested
Moreover, thatthecompound (41) mightthat
authors suggested act through
compound inhibition
(41) mightof mycobacterial
act through
DNA-dependent
inhibition RNA polymerase
of mycobacterial DNA-dependent [67]. The RNAbenzoxazole
polymerasederivative (42) also showed
[67]. The benzoxazole to be
derivative a
(42)
promising
also showed antituberculosis
to be a promising agent. The MIC90 evaluated
antituberculosis agent. The for this
MICcompound
90 evaluated wasfor 3.2 μM
this against
compound XDR-
was
TB µM
3.2 strains and it
against demonstrated
XDR-TB strains andin vivo activity similar
it demonstrated to that
in vivo of RMP
activity in a mouse
similar to thatmodel
of RMP infected with
in a mouse
the selectable
model infectedmarker-free autoluminescent
with the selectable marker-free Mtbautoluminescent
strain H37Ra [68]. Mtb strain H37Ra [68].
drug discovery
The drug discoveryprocess
processisishighly
highlycomplex
complex and
and involves
involves several
several steps.
steps. Among
Among thesethese steps,
steps, the
the determination
determination of theofphysicochemical
the physicochemical propertiesproperties of potentially
of potentially active compounds
active compounds plays an
plays an important
important
role in therole in the
initial initial
stages stages Indeed,
[70,71]. [70,71]. Indeed, some authors
some authors suggestsuggest that bioactive
that bioactive compounds
compounds with
with adequate
adequate physicochemical
physicochemical properties properties
should be should be prioritized
prioritized rather thanrather highlythan active highly
compoundsactive
compounds
with withphysicochemical
inadequate inadequate physicochemical
properties [72].properties [72]. Currently,
Currently, several computational several computational
programs predict
programs
these predict
properties theseonproperties
based databases based on databases
of compounds of compounds
and mathematical and mathematical
formulas formulas
[73,74]. Therefore, we
[73,74]. Therefore, we subjected the most active compounds described
subjected the most active compounds described in this review with MIC90 values below 0.1 µM to an in this review with MIC 90
values below
analysis of the0.1 μM to anrule,
Lipinski’s analysis
whichofindicates
the Lipinski’s
whether rule, which indicates
a molecule could be whether
an orally a molecule
active drugcouldin
be an orally
humans active
[75,76]. We drug in humans
calculated [75,76].
theoretical We calculated
partition coefficient theoretical partition
(cLogP) values, coefficient
molecular (cLogP)
weight and
values, molecular
number of hydrogen weight
bondand number
donors and of hydrogen
acceptors bond
using thedonors
software andOSIRIS
acceptors using the (Table
DataWarrior software 1).
OSIRIS
The dataDataWarrior
showed that (Table 1). The
the majority datacompounds
of the showed that the majority
presented adequate of the compounds
properties presented
according to the
adequate properties
Lipinski’s according
rule. In addition, to the Lipinski’s
the software rule. the
also predicted In addition,
drug-likeness the software also predicted
of these compounds. the
Briefly,
drug-likeness
this drug propertyof these compounds.
indicates whether aBriefly,compound this contains
drug propertyfragments indicates
that arewhether
frequently a compound
present in
contains fragments that are frequently present in commercial drugs. The most active compounds
commercial drugs.
Pharmaceuticals 2017,The
10, xmost active compounds selected presented values of drug-likeness12
inofa17range
of −14.43 to 7.03. The majority of marketed drugs show values between −5 and 5 [77].
selected presented values of drug-likeness in a range of −14.43 to 7.03. The majority of marketed drugs
show values between
Table −5 values and calculated physicochemical parameters.1
and 590[77].
1. MIC
MIC90 (µM)Table 1. MIC390 values and calculated

Donors physicochemical parameters.
2 1
Compound cLogP H bond H bond Acceptors Molecular Weight Drug-Likeness
1 Compound 0.03
MIC90 (μM) 2 1.84 3 H bond Donors
cLogP 0 9
H bond Acceptors 358.33
Molecular Weight −4.43
Drug-Likeness
2 1 0.06 0.03 1.22
1.84 0 0 9 11 358.33419.39 −4.43 −3.14
4 2 0.03 0.06 2.57
1.22 0 0 11 9 419.39437.22 −3.14 −6.22
16 4 0.01 0.03 2.83
2.57 0 1 9 7 437.22473.55 −6.22 7.03
17 16 0.09 0.01 2.98
2.83 1 1 7 5 473.55388.26 7.03 1.53
19 17 0.05 0.09 3.75
2.98 1 1 5 5 388.26401.25 1.53 −1.04
20 19 0.001 0.05 4.23
3.75 1 1 5 5 401.25364.44 −1.04 −1.44
32
20
0.03
0.001
1.23
4.23 1
0
5
7
364.44
433.43
−1.44
−14.4
35 0.08 3.44 1 5 376.89 3.49
32 0.03 1.23 0 7 433.43 −14.4
38 0.006 3.72 2 3 332.39 −1.2
35 0.08 3.44 1 5 376.89 3.49
1
38 0.006Theoretical
3.72calculated values
2 using OSIRIS
3 DataWarrior program.
332.39 −1.2
2 Minimum inhibitory concentration.
1 Theoretical calculated values using OSIRIS DataWarrior program.
3 Calculated partition coefficient.
2 Minimum inhibitory concentration.
3 Calculated partition coefficient.
During drug development, lipophilicity is the most important physicochemical property that
might be analyzed for tuberculosis drug discovery because this property can affect the solubility,
During drug development, lipophilicity is the most important physicochemical property that
permeability and bioavailability of compounds [78]. Furthermore, lipophilicity is recognized to impact
might be analyzed for tuberculosis drug discovery because this property can affect the solubility,
on a number of drug-like characteristics including pharmacokinetics and toxicology properties [79,80].
permeability and bioavailability of compounds [78]. Furthermore, lipophilicity is recognized to
For instance, compounds with high lipophilicity have been related to hepatotoxicity and undesirable
impact on a number of drug-like characteristics including pharmacokinetics and toxicology
non-specific interactions
properties [79,80]. For [81,82]. Nevertheless,
instance, compounds highly
withlipophilic compounds
high lipophilicity should
have beennot be discarded
related to
in screening programs for antituberculosis drugs. One example is the drug bedaquiline,
hepatotoxicity and undesirable non-specific interactions [81,82]. Nevertheless, highly lipophilic which has a
cLogP value of 7.3.
compounds shouldLikewise, low lipophilicity
not be discarded is not
in screening an impediment
programs to tuberculosis
for antituberculosis drug
drugs. One discovery,
example
is the drug
considering bedaquiline,
the number which has
of approved a cLogP
drugs value
with low of 7.3. Likewise,
lipophilicity, low isoniazid
including lipophilicity −0.67),
is not= an
(cLogP
impediment to tuberculosis drug discovery, considering the number of approved
ethambutol (cLogP = 0.12), pyrazinamide (cLogP = −0.68), kanamycin (cLogP = −5.2) and cycloserine drugs with low
(cLogPlipophilicity,
= −1.2). including
Therefore,isoniazid (cLogP
we have = −0.67), the
evaluated ethambutol (cLogPbetween
relationship = 0.12), pyrazinamide
MIC values(cLogP =
and cLogP
−0.68), kanamycin (cLogP = −5.2) and cycloserine (cLogP = −1.2). Therefore, we have evaluated the
(Figure 14). The data showed that the majority of active compounds described in this review presented
relationship between MIC values and cLogP (Figure 14). The data showed that the majority of active
cLogP values in a range from 2 to 6.
compounds described in this review presented cLogP values in a range from 2 to 6.
Figure 14. Correlation between MIC values and cLogP for the compounds. cLogP: calculated
Figure 14. Correlation between MIC values and cLogP for the compounds. cLogP: calculated
partition coefficient.
partition coefficient.
3. Conclusions
Phenotypic screening seems to be a more promising approach to identify compounds active
against MDR-TB than the target-based approach. Despite this, the search for new compounds active
against resistant-TB remains a challenge. The molecular mechanism involved in the resistance
and its possible targets is still not completely understood. However, even in this complicated
scenario, in recent years, active compounds against resistant strains have been found at nanomolar
concentrations. In addition, in vivo studies have shown that some of these compounds exhibited
adequate pharmacokinetics for investigation in future studies. Additional efforts must be made in
order to create strong networks worldwide to discover new drugs against this terrible disease.
Acknowledgments: The authors thank the Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP grants 2016/09502-7) for financial support.
Author Contributions: Authors G.F.d.S.F. and J.L.S. designed the study, analyzed and organized the literature
papers. C.M.C. and J.L.S. revised the manuscript and approved it in its final form. All authors edited and
contributed to drafts of the manuscript. All authors approved the final form of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. World Health Organization. Global Tuberculosis Report; World Health Organization: Geneva, Switzerland, 2015.
2. World Health Organization. Global Tuberculosis Report 2014 (WHO/HTM/TB/2014.08); World Health
Organization: Geneva, Switzerland, 2014.
3. Zumla, A.; Nahid, P.; Cole, S.T. Advances in the development of new tuberculosis drugs and treatment
regimens. Nat. Rev. Drug Discov. 2013, 12, 388–404. [CrossRef] [PubMed]
4. Klopper, M.; Warren, R.M.; Hayes, C.; van Pittius, N.C.G.; Streicher, E.M.; Muller, B.; Sirgel, F.A.;
Chabula-Nxiweni, M.; Hoosain, E.; Coetzee, G.; et al. Emergence and spread of extensively and totally
drug-resistant tuberculosis, South Africa. Emerg. Infect. Dis. 2013, 19, 449–455. [CrossRef] [PubMed]
5. Slomski, A. South Africa Warns of Emergence of “Totally” Drug-Resistant Tuberculosis. J. Am. Med. Assoc.
2013, 309, 1097–1098. [CrossRef] [PubMed]
6. Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. The challenge of new drug discovery for
tuberculosis. Nature 2011, 469, 483–490. [CrossRef] [PubMed]
7. Fernandes, G.F.S.; Jornada, D.H.; Souza, P.C.; Man Chin, C.; Pavan, F.R.; Santos, J.L. Current Advances in
Antitubercular Drug Discovery: Potent Prototypes and New Targets. Curr. Med. Chem. 2015, 22, 3133–3161.
[CrossRef]
8. Pai, M.; Behr, M.A.; Dowdy, D.; Dheda, K.; Divangahi, M.; Boehme, C.C.; Ginsberg, A.; Swaminathan, S.;
Spigelman, M.; Getahun, H.; et al. Tuberculosis. Nat. Rev. Dis. Prim. 2016, 2, 1–23. [CrossRef] [PubMed]
9. Wallis, R.S.; Maeurer, M.; Mwaba, P.; Chakaya, J.; Rustomjee, R.; Migliori, G.B.; Marais, B.; Schito, M.;
Churchyard, G.; Swaminathan, S.; et al. Tuberculosis—Advances in development of new drugs, treatment
regimens, host-directed therapies, and biomarkers. Lancet Infect. Dis. 2016, 16, e34–e46. [CrossRef]
10. Bloemberg, G.V.; Keller, P.M.; Stucki, D.; Trauner, A.; Borrell, S.; Latshang, T.; Coscolla, M.; Rothe, T.;
Hömke, R.; Ritter, C.; et al. Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis.
N. Engl. J. Med. 2015, 373, 1986–1988. [CrossRef] [PubMed]
11. Zhang, S.; Chen, J.; Cui, P.; Shi, W.; Shi, X.; Niu, H.; Chan, D.; Yew, W.W.; Zhang, W.; Zhang, Y. Mycobacterium
tuberculosis Mutations Associated with Reduced Susceptibility to Linezolid. Antimicrob. Agents Chemother.
2016, 60, 2542–2544. [CrossRef] [PubMed]
12. Segala, E.; Sougakoff, W.; Nevejans-Chauffour, A.; Jarlier, V.; Petrella, S. New mutations in the mycobacterial
ATP synthase: New insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-Ring
structure. Antimicrob. Agents Chemother. 2012, 56, 2326–2334. [CrossRef] [PubMed]
13. Karabanovich, G.; Zemanova, J.; Smutny, T.; Szekely, R.; Sarkan, M.; Centarova, I.; Vocat, A.; Pavkova, I.;
Conka, P.; Nemecek, J.; et al. Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as
Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis.
J. Med. Chem. 2016, 59, 2362–2380. [CrossRef] [PubMed]
14. Karabanovich, G.; Němeček, J.; Valášková, L.; Carazo, A.; Konečná, K.; Stolaříková, J.; Hrabálek, A.; Pavliš, O.;
Pávek, P.; Vávrová, K.; et al. S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols
as highly efficient antitubercular agents. Eur. J. Med. Chem. 2017, 126, 369–383. [CrossRef] [PubMed]
15. Zurenko, G.E.; Gibson, J.K.; Shinabarger, D.L.; Aristoff, P.A.; Ford, C.W.; Tarpley, W.G. Oxazolidinones:
A new class of antibacterials. Curr. Opin. Pharmacol. 2001, 1, 470–476. [CrossRef]
16. Wilson, D.N.; Schluenzen, F.; Harms, J.M.; Starosta, A.L.; Connell, S.R.; Fucini, P. The oxazolidinone
antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc. Natl. Acad.
Sci. USA 2008, 105, 13339–13344. [CrossRef] [PubMed]
17. Balasubramanian, V.; Solapure, S.; Iyer, H.; Ghosh, A.; Sharma, S.; Kaur, P.; Deepthi, R.; Subbulakshmi, V.;
Ramya, V.; Ramachandran, V.; et al. Bactericidal activity and mechanism of action of AZD5847, a novel
oxazolidinone for treatment of tuberculosis. Antimicrob. Agents Chemother. 2014, 58, 495–502. [CrossRef]
[PubMed]
18. Furin, J.J.; Bois, D.; Van Brakel, E.; Chheng, P.; Venter, A.; Peloquin, C.A.; Alsultan, A.; Thiel, B.A.;
Debanne, S.M.; Boom, W.H.; et al. Early Bactericidal Activity of AZD5847 in Patients with Pulmonary
Tuberculosis. Antimicrob. Agents Chemother. 2016, 60, 6591–6599. [CrossRef] [PubMed]
19. Ang, W.; Ye, W.; Sang, Z.; Liu, Y.; Yang, T.; Deng, Y.; Luo, Y.; Wei, Y. Discovery of novel bis-oxazolidinone
compounds as potential potent and selective antitubercular agents. Bioorg. Med. Chem. Lett. 2014, 24,
1496–1501. [CrossRef] [PubMed]
20. Gobis, K.; Foks, H.; Serocki, M.; Augustynowicz-Kopec, E.; Napiorkowska, A. Synthesis and evaluation of
in vitro antimycobacterial activity of novel 1H-benzo[d]imidazole derivatives and analogues. Eur. J. Med. Chem.
2014, 89, 13–20. [CrossRef] [PubMed]
21. Gobis, K.; Foks, H.; Suchan, K.; Augustynowicz-Kopec, E.; Napiorkowska, A.; Bojanowski, K. Novel
2-(2-phenalkyl)-1H-benzo[d]imidazoles as antitubercular agents. Synthesis, biological evaluation and
structure-activity relationship. Bioorg. Med. Chem. 2015, 23, 2112–2120. [CrossRef] [PubMed]
22. Kravchenko, M.A.; Verbitskiy, E.V.; Medvinskiy, I.D.; Rusinov, G.L.; Charushin, V.N. Synthesis and
antituberculosis activity of novel 5-styryl-4-(hetero)aryl- pyrimidines via combination of the Pd-catalyzed
Suzuki cross-coupling and S NH reactions. Bioorg. Med. Chem. Lett. 2014, 24, 3118–3120. [CrossRef]
[PubMed]
23. Verbitskiy, E.V.; Baskakova, S.A.; Kravchenko, M.A.; Skornyakov, S.N.; Rusinov, G.L.; Chupakhin, O.N.;
Charushin, V.N. Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(hetero)aryl
substituted pyrimidines. Bioorg. Med. Chem. 2016, 24, 3771–3780. [CrossRef] [PubMed]
24. Tonelli, M.; Novelli, F.; Tasso, B.; Sparatore, A.; Boido, V.; Sparatore, F.; Cannas, S.; Molicotti, P.;
Zanetti, S.; Parapini, S.; et al. Antitubercular activity of quinolizidinyl/pyrrolizidinylalkyliminophenazines.
Bioorg. Med. Chem. 2014, 22, 6837–6845. [CrossRef] [PubMed]
25. Chatterji, M.; Shandil, R.; Manjunatha, M.R.; Solapure, S.; Ramachandran, V.; Kumar, N.; Saralaya, R.;
Panduga, V.; Reddy, J.; Prabhakar, K.R.; et al. 1,4-azaindole, A potential drug candidate for treatment of
tuberculosis. Antimicrob. Agents Chemother. 2014, 58, 5325–5331. [CrossRef] [PubMed]
26. Shirude, P.S.; Shandil, R.; Sadler, C.; Naik, M.; Hosagrahara, V.; Hammed, S.; Shinde, V.; Bathula, C.;
Humnabadkar, V.; Kumar, N.; et al. Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing
Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo. J. Med. Chem. 2013, 56, 9701–9708.
[CrossRef] [PubMed]
27. Velezheva, V.; Brennan, P.; Ivanov, P.; Kornienko, A.; Lyubimov, S.; Kazarian, K.; Nikonenko, B.; Majorov, K.;
Apt, A. Synthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones,
and thiosemicarbazones. Bioorg. Med. Chem. Lett. 2016, 26, 978–985. [CrossRef] [PubMed]
28. Danac, R.; Mangalagiu, I.I. Antimycobacterial activity of nitrogen heterocycles derivatives: Bipyridine
derivatives. Part III. Eur. J. Med. Chem. 2014, 74, 664–670. [CrossRef] [PubMed]
29. Panda, M.; Ramachandran, S.; Ramachandran, V.; Shirude, P.S.; Humnabadkar, V.; Nagalapur, K.; Sharma, S.;
Kaur, P.; Guptha, S.; Narayan, A.; et al. Discovery of pyrazolopyridones as a novel class of noncovalent
DprE1 inhibitor with potent anti-mycobacterial activity. J. Med. Chem. 2014, 57, 4761–4771. [CrossRef]
[PubMed]
30. Riccardi, G.; Pasca, M.R.; Chiarelli, L.R.; Manina, G.; Mattevi, A.; Binda, C. The DprE1 enzyme, one of the
most vulnerable targets of Mycobacterium tuberculosis. Appl. Microbiol. Biotechnol. 2013, 97, 8841–8848.
[CrossRef] [PubMed]
31. Brecik, M.; Centárová, I.; Mukherjee, R.; Kolly, G.S.; Huszár, S.; Bobovská, A.; Kilacsková, E.; Mokošová, V.;
Svetlíková, Z.; Šarkan, M.; et al. DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall
Localization. ACS Chem. Biol. 2015, 10, 1631–1636. [CrossRef] [PubMed]
32. Tang, J.; Wang, B.; Wu, T.; Wan, J.; Tu, Z.; Njire, M.; Wan, B.; Franzblauc, S.G.; Zhang, T.; Lu, X.; et al. Design,
Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular
Agents. ACS Med. Chem. Lett. 2015, 6, 814–818. [CrossRef] [PubMed]
33. Wu, Z.; Lu, Y.; Li, L.; Zhao, R.; Wang, B.; Lv, K.; Liu, M.; You, X. Identification of N -(2-Phenoxyethyl)
imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents. ACS Med. Chem. Lett. 2016, 7,
34. Bhakta, S.; Scalacci, N.; Maitra, A.; Brown, A.K.; Dasugari, S.; Evangelopoulos, D.; McHugh, T.D.;
Mortazavi, P.N.; Twist, A.; Petricci, E.; et al. Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-
1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N0 -((E)-3,7-dimethylocta-2,6-dienyl)
ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antituberc. J. Med. Chem. 2016, 59,
35. Singh, S.; Kaur, G.; Mangla, V.; Gupta, M.K. Quinoline and quinolones: Promising scaffolds for future
antimycobacterial agents. J. Enzym. Inhib. Med. Chem. 2015, 30, 492–504. [CrossRef] [PubMed]
36. Pissinate, K.; Villela, A.D.; Rodrigues, V.; Giacobbo, B.C.; Grams, E.S.; Abbadi, B.L.; Trindade, R.V.; Roesler
Nery, L.; Bonan, C.D.; Back, D.F.; et al. 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible
and Drug-Resistant Mycobacterium tuberculosis Strains. ACS Med. Chem. Lett. 2016, 7, 235–239. [CrossRef]
[PubMed]
37. Giacobbo, B.C.; Pissinate, K.; Rodrigues-Junior, V.; Villela, A.D.; Grams, E.S.; Abbadi, B.L.; Subtil, F.T.;
Sperotto, N.; Trindade, R.V.; Back, D.F.; et al. New insights into the SAR and drug combination synergy of
2-(quinolin-4-yloxy)acetamides against Mycobacterium tuberculosis. Eur. J. Med. Chem. 2017, 126, 491–501.
[CrossRef] [PubMed]
38. Naik, M.; Humnabadkar, V.; Tantry, S.J.; Panda, M.; Narayan, A.; Guptha, S.; Panduga, V.; Manjrekar, P.;
Jena, L.K.; Koushik, K.; et al. 4-Aminoquinolone piperidine amides: Noncovalent inhibitors of DprE1 with
long residence time and potent antimycobacterial activity. J. Med. Chem. 2014, 57, 5419–5434. [CrossRef]
[PubMed]
39. Lu, W.; Baig, I.A.; Sun, H.J.; Cui, C.J.; Guo, R.; Jung, I.P.; Wang, D.; Dong, M.; Yoon, M.Y.; Wang, J.G. Synthesis,
crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis
agents targeting acetohydroxyacid synthase. Eur. J. Med. Chem. 2015, 94, 298–305. [CrossRef] [PubMed]
40. Gokhale, K.; Tilak, B. Mechanisms of bacterial acetohydroxyacid synthase (AHAS) and specific inhibitors of
Mycobacterium tuberculosis AHAS as potential drug candidates against tuberculosis. Curr. Drug Targets
2015, 16, 689–699. [CrossRef] [PubMed]
41. Mukherjee, T.; Boshoff, H. Nitroimidazoles for the treatment of TB: Past, present and future. Futur. Med. Chem.
2011, 3, 1427–1454. [CrossRef] [PubMed]
42. Rakesha, D.B.; Madhura, D.B.; Maddox, M.; Lee, R.B.; Trivedi, A.; Yang, L.; Scherman, M.S.; Gilliland, J.C.;
Gruppo, V.; McNeil, M.R.; et al. Antitubercular nitrofuran isoxazolines with improved pharmacokinetic
properties. Bioorg. Med. Chem. 2012, 20, 6063–6072. [CrossRef] [PubMed]
43. Hernández, P.; Rojas, R.; Gilman, R.H.; Sauvain, M.; Lima, L.M.; Barreiro, E.J.; González, M.; Cerecetto, H.
Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug
candidates. Eur. J. Med. Chem. 2013, 59, 64–74. [CrossRef] [PubMed]
44. Krasavin, M.; Parchinsky, V.; Kantin, G.; Manicheva, O.; Dogonadze, M.; Vinogradova, T.; Karge, B.;
Brönstrup, M. New nitrofurans amenable by isocyanide multicomponent chemistry are active against
multidrug-resistant and poly-resistant Mycobacterium tuberculosis. Bioorg. Med. Chem. 2017, 25, 1867–1874.
[CrossRef] [PubMed]
45. Lewis, J.M.; Sloan, D.J. The role of delamanid in the treatment of drug-resistant tuberculosis. Ther. Clin.
Risk Manag. 2015, 11, 779–791. [PubMed]
46. Xavier, A.S.; Lakshmanan, M. Delamanid: A new armor in combating drug-resistant tuberculosis.
J. Pharmacol. Pharmacother. 2014, 5, 222–224. [CrossRef] [PubMed]
47. Munagala, G.; Yempalla, K.R.; Singh, S.; Sharma, S.; Kalia, N.P.; Rajput, V.S.; Kumar, S.;
Sawant, S.D.; Khan, I.A.; Vishwakarma, R.A.; et al. Synthesis of new generation triazolyl- and
isoxazolyl-containing 6-nitro-2,3-dihydroimidazooxazoles as anti-TB agents: In vitro, structure-activity
relationship, pharmacokinetics and in vivo evaluation. Org. Biomol. Chem. 2015, 13, 3610–3624. [CrossRef]
[PubMed]
48. Fernandes, G.F.; de Souza, P.C.; Marino, L.B.; Chegaev, K.; Gugliemo, S.; Lazzarato, L.; Fruttero, R.;
Chung, M.C.; Pavan, F.R.; Dos Santos, J.L. Synthesis and biological activity of furoxan derivatives against
Mycobacterium tuberculosis. Eur. J. Med. Chem. 2016, 123, 523–531. [CrossRef] [PubMed]
49. Papadopoulou, M.V.; Bloomer, W.D.; Rosenzweig, H.S.; Arena, A.; Arrieta, F.; Rebolledo, J.C.J.; Smith, D.K.
Nitrotriazole- and imidazole-based amides and sulfonamides as antitubercular agents. Antimicrob. Agents
Chemother. 2014, 58, 6828–6836. [CrossRef] [PubMed]
50. Van Der Westhuyzen, R.; Winks, S.; Wilson, C.R.; Boyle, G.A.; Gessner, R.K.; Soares De Melo, C.;
Taylor, D.; De Kock, C.; Njoroge, M.; Brunschwig, C.; et al. Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A novel
antimycobacterial class targeting mycobacterial respiration. J. Med. Chem. 2015, 58, 9371–9381. [CrossRef]
[PubMed]
51. Pedgaonkar, G.S.; Sridevi, J.P.; Jeankumar, V.U.; Saxena, S.; Devi, P.B.; Renuka, J.; Yogeeswari, P.; Sriram, D.
Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis
InhA. Bioorganic Med. Chem. 2014, 22, 6134–6145. [CrossRef] [PubMed]
52. Li, D.; Gao, N.; Zhu, N.; Lin, Y.; Li, Y.; Chen, M.; You, X.; Lu, Y.; Wan, K.; Jiang, J.D.; et al. Discovery of
the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR- and XDR-MTB.
Bioorg. Med. Chem. Lett. 2015, 25, 5178–5181. [CrossRef] [PubMed]
53. Krátký, M.; Vinsova, J. Sulphur-Containing Heterocycles as Antimycobacterial Agents: Recent Advances in
Thiophene and Thiadiazole Derivatives. Curr. Top. Med. Chem. 2016, 16, 2921–2952. [CrossRef] [PubMed]
54. Bellale, E.; Naik, M.; Vb, V.; Ambady, A.; Narayan, A.; Ravishankar, S.; Ramachandran, V.; Kaur, P.;
McLaughlin, R.; Whiteaker, J.; et al. Diarylthiazole: An antimycobacterial scaffold potentially targeting
PrrB-PrrA two-component system. J. Med. Chem. 2014, 57, 6572–6582. [CrossRef] [PubMed]
55. Haydel, S.E.; Malhotra, V.; Cornelison, G.L.; Clark-Curtiss, J.E. Transient requirement of the PrrA-PrrB
two-component system for early intracellular multiplication of Mycobacterium tuberculosis. J. Bacteriol.
2012, 194, 354–361. [CrossRef] [PubMed]
56. Ewann, F.; Jackson, M.; Pethe, K.; Cooper, A.; Mielcarek, N.; Ensergueix, D.; Gicquel, B.; Locht, C.; Supply, P.
Transient Requirement of the PrrA-PrrB Two-Component System for Early Intracellular Multiplication of
Mycobacterium tuberculosis. Infect. Immun. 2002, 70, 2256–2263. [CrossRef] [PubMed]
57. Gao, C.; Peng, C.; Shi, Y.; You, X.; Ran, K.; Xiong, L.; Ye, T.; Zhang, L.; Wang, N.; Zhu, Y.; et al.
Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis. Sci. Rep.
2016, 6, 29717. [CrossRef] [PubMed]
58. Makarov, V.; Manina, G.; Mikusova, K.; Möllmann, U.; Ryabova, O.; Saint-Joanis, B.; Dhar, N.; Pasca, M.R.;
Buroni, S.; Lucarelli, A.P.; et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan
synthesis. Science 2009, 324, 801–804. [CrossRef] [PubMed]
59. Pieroni, M.; Wan, B.; Cho, S.; Franzblau, S.G.; Costantino, G. Design, synthesis and investigation on
the structure-activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents.
Eur. J. Med. Chem. 2014, 72, 26–34. [CrossRef] [PubMed]
60. Landge, S.; Mullick, A.B.; Nagalapur, K.; Neres, J.; Subbulakshmi, V.; Murugan, K.; Ghosh, A.;
Sadler, C.; Fellows, M.D.; Humnabadkar, V.; et al. Discovery of benzothiazoles as antimycobacterial
agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis
decaprenylphosphoryl-B-D-ribose 2’-oxidase. Bioorg. Med. Chem. 2015, 23, 7694–7710. [CrossRef] [PubMed]
61. Mahajan, N.S.; Dhawale, S.C. Linked pyridinyl-thiadiazoles: Design and synthesis as potential candidate for
treatment of XDR and MDR tuberculosis. Eur. J. Med. Chem. 2015, 102, 243–248. [CrossRef] [PubMed]
62. Verbitskiy, E.V.; Cheprakova, E.M.; Slepukhin, P.A.; Kravchenko, M.A.; Skornyakov, S.N.; Rusinov, G.L.;
Chupakhin, O.N.; Charushin, V.N. Synthesis, and structure-activity relationship for C(4) and/or C(5) thienyl
substituted pyrimidines, as a new family of antimycobacterial compounds. Eur. J. Med. Chem. 2015, 97,
63. Stec, J.; Vilchèze, C.; Lun, S.; Perryman, A.L.; Wang, X.; Freundlich, J.S.; Bishai, W.; Jacobs, W.R.;
Kozikowski, A.P. Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein
reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. ChemMedChem
2014, 9, 2528–2537. [CrossRef] [PubMed]
64. Stec, J.; Onajole, O.K.; Lun, S.; Guo, H.; Merenbloom, B.; Vistoli, G.; Bishai, W.R.; Kozikowski, A.P.
Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal
Model of Tuberculosis Infection. J. Med. Chem. 2016, 59, 6232–6247. [CrossRef] [PubMed]
65. Naidu, K.M.; Srinivasarao, S.; Agnieszka, N.; Ewa, A.K.; Kumar, M.M.K.; Chandra Sekhar, K.V.G. Seeking
potent anti-tubercular agents: Design, synthesis, anti-tubercular activity and docking study of various
((triazoles/indole)-piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole derivatives. Bioorg. Med. Chem. Lett.
2016, 26, 2245–2250. [CrossRef] [PubMed]
66. Mahajan, P.S.; Nikam, M.D.; Nawale, L.U.; Khedkar, V.M.; Sarkar, D.; Gill, C.H. Synthesis and Antitubercular
Activity of New Benzo[b]thiophenes. ACS Med. Chem. Lett. 2016, 7, 751–756. [CrossRef] [PubMed]
67. Nair, V.; Okello, M.O.; Mangu, N.K.; Seo, B.I.; Gund, M.G. A novel molecule with notable activity against
multi-drug resistant tuberculosis. Bioorg. Med. Chem. Lett. 2015, 25, 1269–1273. [CrossRef] [PubMed]
68. Lu, X.; Hu, X.; Liu, Z.; Zhang, T.; Wang, R.; Wan, B.; Franzblau, S.; You, Q. Benzylsulfanyl benzo-heterocycle
amides and hydrazones as new agents against drug susceptible and resistant Mycobacterium tuberculosis.
Med. Chem. Commun. 2017. [CrossRef]
69. Zheng, R.; Blanchard, J.S. Steady-State and Pre-Steady-State Kinetic Analysis of Mycobacterium tuberculosis
Pantothenate Synthetase. Biochemistry 2001, 40, 12904–12912. [CrossRef] [PubMed]
70. Leeson, P.D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry.
Nat. Rev. Drug Discov. 2007, 6, 881–890. [CrossRef] [PubMed]
71. Curatolo, W. Physical chemical properties of oral drug candidates in the discovery and exploratory
development settings. Pharm. Sci. Technol. Today 1998, 1, 387–393. [CrossRef]
72. Mdluli, K.; Kaneko, T.; Upton, A. Tuberculosis drug discovery and emerging targets. Ann. N. Y. Acad. Sci.
2014, 1323, 56–75. [CrossRef] [PubMed]
73. Wenlock, M.C.; Barton, P. In Silico Physicochemical Parameter Predictions. Mol. Pharm. 2013, 10, 1224–1235.
[CrossRef] [PubMed]
74. Tetko, I.V. Computing chemistry on the web. Drug Discov. Today 2005, 10, 1497–1500. [CrossRef]
75. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to
estimate solubility and permeability in drug discovery and developmental settings. Adv. Drug Deliv. Rev.
1997, 23, 3–25. [CrossRef]
76. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to
estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001,
46, 3–26. [CrossRef]
77. Organic Chemistry Portal Fragment Based Druglikeness. Available online: http://www.organic-chemistry.
org/prog/peo/druglike (accessed on 29 May 2017).
78. Zuniga, E.S.; Early, J.; Parish, T. The future for early-stage tuberculosis drug discovery. Futur. Microbiol. 2015,
10, 217–229. [CrossRef] [PubMed]
79. Manjunatha, U.H.; Smith, P.W. Perspective: Challenges and opportunities in TB drug discovery from
phenotypic screening. Bioorg. Med. Chem. 2015, 23, 5087–5097. [CrossRef] [PubMed]
80. Waring, M.J. Lipophilicity in drug discovery. Expert Opin. Drug Discov. 2010, 5, 235–248. [CrossRef]
[PubMed]
81. Chen, M.; Borlak, J.; Tong, W. High lipophilicity and high daily dose of oral medications are associated with
significant risk for drug-induced liver injury. Hepatology 2013, 58, 388–396. [CrossRef] [PubMed]
82. Tarcsay, A.; Keserű, G.M. Contributions of molecular properties to drug promiscuity. J. Med. Chem. 2013, 56,
© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Anti-Tuberculosis Compounds

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Anti-Tuberculosis Compounds

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pharmaceuticals

Academic Editor: Jean Jacques Vanden Eynde

Keywords: tuberculosis; drug discovery; antitubercular compounds; multidrug-resistant tuberculosis

Pharmaceuticals 2017, 10, 51; doi:10.3390/ph10020051 www.mdpi.com/journal/pharmaceuticals

Oxazolidinone is an important class of antibiotic used for treatment of infections caused by

Pharmaceuticals 2017, 10, x 6 of 17

Figure 7. Quinoline derivatives with antituberculosis activity.

Figure 10. Heterocyclic compounds as promising agents for the treatment

Sulfur-containing heterocycles have been widely exploited as antituberculosis agents [53].

For instance, compound (39) exhibited MIC90 90 of

MIC90 (µM)Table 1. MIC390 values and calculated

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